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Huntington's disease
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2009 - 2010 One year pilot study Fibroblasts as a new disease model for Huntington’s disease to replace and reduce the use of animalsDr O. Bandmann & Dr H. Mortiboys |
Dr Bandmann is Senior Lecturer in Neurology (clinical) and Honorary Consultant Neurologist in the School of Medicine, Sheffield University.
Dr Mortiboys is a post-doctoral Research Associate in the Academic Neurology Unit at Sheffield University
Transgenic mice engineered to have Huntington’s Disease (HD), HD rats and more recently also HD primates[1] have been created, but these only partially reflect the changes observed in human patients and have not as yet led to the discovery of disease-modifying treatments.
HD is a relentlessly progressive, incurable brain disease. Patients with this disorder typically develop a combination of motor impairment (chorea, dystonia and impaired balance), depression, aggressive outbursts, dementia and personality change. Pharmacological or other therapeutic intervention only partially and temporarily improves certain symptoms. No medication is available which would delay the disease onset or slow down the disease-progression. The discovery of such disease-modifying therapy would be of considerable benefit to both the patients and their families.
HD is a monogenically inherited illness caused by a trinucleotide expansion in the Huntingtin gene IT15: Unaffected controls have up to 35 CAG repeats (encoding glutamine), patients with HD typically have 40 or more CAG repeats (patients with 60 or more CAG repeats typically develop early onset HD).
There is strong evidence for impaired mitochondrial function in Huntington’s disease (HD). ATP levels were markedly reduced and mitochondrial morphology significantly changed in fibroblasts of HD patients with comparatively large CAG expansion (60-70 CAG repeats). The overall aim of this study is to establish skin fibroblasts as a new HD model system, to both study important mechanisms contributing to the pathogenesis of HD and rapidly screen for disease-modifying compounds.
The objectives are to:
- Determine mitochondrial membrane potential, ATP levels and mitochondrial morphology in 10 patients with typical CAG repeat length (40-50 repeats);
- Evaluate whether the transcription of a crucial regulator of mitochondrial function, PGC-1? is downregulated in HD fibroblasts (as previously observed in HD brains);
- Assess whether either global pharmacological inhibition of histone deacetylase inhibitors (HDAC) or siRNA-mediated specific HDAC inhibition corrects impaired mitochondrial function and morphology.
The aim of this research project is to determine the usefulness of HD mutant skin fibroblasts as a new model to both screen for disease-modifying compounds and further determine important mechanisms leading to HD. If it can be demonstrated that these HD mutant fibroblasts are indeed useful tools for such studies, then this could contribute to very significant replacement of animals currently used for HD related studies.
References
[1] Yang S-H, Cheng P-H, Banta H, et al. (2008): Towards a transgenic model of Huntington’s Disease in a non-human primate. Nature 453:921-925.